Synergistic Effect of the TiCl4/p-TsOH Promoter System on the Aza-Prins Cyclization

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Synergistic Effect of the TiCl4/p-TsOH Promoter System on the Aza-Prins Cyclization

Vianney Durel, Claudia Lalli, Thierry Roisnel, Pierre van de Weghe

To cite this version:

Vianney Durel, Claudia Lalli, Thierry Roisnel, Pierre van de Weghe. Synergistic Effect of the TiCl4/p- TsOH Promoter System on the Aza-Prins Cyclization. Journal of Organic Chemistry, American Chemical Society, 2016, 81 (3), pp.849-859. �10.1021/acs.joc.5b02342�. �hal-01256843�

Synergistic effect of the TiCl4/p-TsOH promoter system on the Aza-Prins cyclization

Vianney Durel, Claudia Lalli,* Thierry Roisnel and Pierre van de Weghe*

Université de Rennes 1, UMR CNRS 6226, Institut des Sciences Chimiques de Rennes, Equipe PNSCM, UFR des Sciences Biologiques et Pharmaceutiques, 2 avenue du Prof Léon Bernard, F- 35043 Rennes Cedex, France

*E-mail: [email protected]

*E-mail: [email protected]

Table of Contents artwork

Abstract A novel aza-Prins cyclization promoted by a synergistic combination between a Lewis acid and a Brønsted acid to efficiently afford piperidines is described. Contrary to what has been previously reported in the literature, the generality of the reaction employing N-alkyl, N-aryl and non-protected homoallylamines has been demonstrated. The reaction is highly diastereoselective depending on the homoallylic amine used, N-PMP homoallyl amine leading preferentially to the trans diastereomer, and free homoallylamine affording the deprotected piperidine as single cis diastereomer.

Introduction

Nowadays there are many routes to prepare piperidines, among them the aza-Prins cyclization reaction involving aldehydes and homoallylic amines, appears to be a straightforward method that provides direct access to six-membered azacycles.¹ Despite the great interest and the recent advances concerning the Prins cyclization, a feasible nitrogen-based version of this reaction knows only moderate success. Indeed this reaction is restricted in most cases to N-sulfonyl homoallylic amines, which may limit the interest in this process and its development. Several Lewis acids are reported to promote the reaction of N-sulfonyl homoallylic amines with aldehydes, among them, Fe(III) halides in stoichiometric or sub-stoichiometric amount,² BiCl3,³ BF3.Et2O, ⁴ InCl3

5 and TMSX.⁶ Brønsted acids are also reported to catalyze the cyclization, as in the case of phosphomolybdic acid,⁷ HBF4.Et2O⁸ and TfOH.⁹ It has to be pointed out that there are only a very few examples reported in the literature concerning aliphatic or primary amines.¹⁰ They concern mainly the use of the aza-Prins cyclization as key step in the total synthesis of biologically active alkaloids. To the best of our knowledge to date a detailed study devoted to the development of an effective aza-Prins cyclization involving non- sulfonylated homoallylic amines has not been undertaken. We wish herein to fill this gap by reporting our results on the aza-Prins cyclization reaction with N-aryl, -alkyl homoallylic amines and even with non-protected ones.

Results

We began our investigations by studying the reaction between N-alkyl homoallylic amine as model substrate, namely N-methyl but-3-en-1-ylglycinate (1), and p-bromobenzaldehyde (2a), in CH2Cl2 at 60 °C in a sealed vial overnight (table 1). In the first attempts different Lewis acids known to promote

the aza-Prins cyclization were screened, such as FeCl3, AlCl3 or Bi(OTf)3 (entries 1-3), unfortunately without any conversion of the starting materials, in some cases only the degradation of the reagents after a prolonged reaction time was observed. Only with 3 equiv. of MgBr2 or TiCl4 (entry 4-5) trace amounts of the desired product were detected in the crude NMR. The use of p-TsOH.H2O, TFA and p- nitrobenzoic acid as Brønsted acids (entries 6-8) also failed to convert the starting materials into the desired product.

Table 1. Reaction conditions optimization.^[a]

Entry Lewis Acid

(equiv.) Brønsted Acid

(equiv.) Yield (%)^[b] Cis:trans

(d.r.)^[d] X

1 FeCl3 (3) - n.r.^[c] - -

2 AlCl3 (3) - n.r.^[c] - -

3 Bi(OTf)3 (3) - n.r.^[c] - -

4 MgBr2 (3) - traces - Br

5 TiCl4 (3) - traces - Cl

6 - p-TsOH.H2O (3) n.r.^[c] - -

7 - TFA (3) n.r.^[c] - -

8 - p-NO2-C6H4CO2H n.r.^[c] - -

9 TiCl4 p-TsOH.H2O (1) 98 57:43 Cl

10 TiCl4(1) p-TsOH.H2O (0.1) 99 57:43 Cl

11 MgBr2 (1) p-TsOH.H2O (0.1) 55 50:50 Br

12 AlCl3 (1) p-TsOH.H2O (0.1) 43 45:55 Cl

13 FeCl3 (1) p-TsOH.H2O (0.1) 28 50:50 Cl

14 ZnCl2 (1) p-TsOH.H2O (0.1) 20 50:50 Cl

[a] General conditions: 1 (1 equiv.), 2a (1 equiv.), CH2Cl2 (0.05 M) at 60 °C 16 h. [b] Yields refer to isolated products. [c] n.r.: no reaction. [d] ¹H NMR determination on the crude mixture.

Within our recent investigations on the Prins cyclization,¹¹ we reported a remarkable synergistic effect between non-reactive Brønsted and Lewis acids that lack the ability to catalyze the reaction if used alone.^11b The benefit of this synergistic effect in the Prins cyclization was then confirmed when we disclosed the first enantioselective Prins cyclization by combining a chiral BINOL-derived bis- phosphoric acid and CuCl.^11c

Based on our findings and on the previous observations by Aubé and coworkers,^{10 a,b} we decided to combine TiCl4 with p-TsOH.H2O, the Lewis acid playing the role also of the nucleophile source. Thus 1, and 2a were reacted in the presence of 3 equiv. of TiCl4 and 1 equiv. of p-TsOH.H2O, in CH2Cl2 at 60 °C in a sealed vial overnight (table 1, entry 9). To our delight the desired product was recovered in 98% yield, as a mixture of two diastereomers (cis:trans = 57:43). The variation of the Lewis and Brønsted acid amounts didn’t affect the reactivity (see supporting information for details) and gratifyingly the expected piperidine was recovered in quantitative yield even with only 1 equiv. of TiCl4 and catalytic amount (10 mol%) of p-TsOH.H2O and in the same diastereomeric ratio (table 1, entry 10). A screening of different Brønsted and Lewis acid combinations revealed TiCl4 to be superior to MgBr2, AlCl3, FeCl3 and ZnCl2 (table 1, entries 11-14). On the contrary, the use of TFA, MeSO3H, camphorsulfonic acid, as well as p-nitro benzoic acid with TiCl4 didn't affect the outcome of the reaction (see Supporting Information for details). Decreasing the reaction temperature to 40 °C was detrimental for the reactivity, moreover when the reaction was performed at 60 °C in 1,2- dichloroethane a slight drop of the yield was observed.

With the optimized conditions in hand we next examined the scope of the synergism between TiCl4

and p-TsOH.H2O with respect to different aldehydes, and the results are summarized in Table 2.

Table 2. Scope of the aza-Prins cyclization with the N-alkyl homoallylic amine 1.^a

NH

MeO₂C +

N Cl

R

trans3

1 2

cis3 MeO₂C

RCHO +

N Cl

R MeO₂C

TiCl₄(1 equiv) p-TsOH.H2O (10 mol%)

CH₂Cl₂, 60 °C (sealed tube)

16 h

Entry Aldehyde 2 R= Product 3 Yield (%)^[b] Cis:trans (d.r.)^[c]

1 p-Br-C6H4 2a

3a

98 57:43

2 C6H5 2b

3b

94 57:43

3 o-Cl-C6H4 2c

3c

86 86:14

4 p-CN-C6H4 2d

3d

96 42:58

5 p-NO2-C6H4 2e

3e

90 38:62

6 m-NO2-C6H4 2f

3f

97 45:55

7 p-N(CH3)2-C6H4 2g

3g

60 50:50

8 2,5-(OCH3)2-C6H3 2h

3h

92 87:13

9 o-OCH3-C6H4 2i _N

Cl

MeO2C

OMe

3i

65 85:15

10 p-OCH3-C6H4 2j

3j

60^[d] 62:38

11 p-CH3-C6H4 2k

3k

74 62:38

12 (CH3)2CH 2l

3l

86 43:57

13^[e] C6H4-(CH2)2 2m

3m

52 62:38

14^[e] (CH3)(CH2)6 2n

3n

78 62:38

[a] General conditions: 1 (1 equiv.), 2 (1 equiv.), TiCl4 (1 equiv.), p-TsOH.H2O (10 mol%), in CH2Cl2

(0.1 M) at 60 °C in a sealed vial 16 h. [b] Yields refer to isolated products. [c] ¹H NMR determination on the crude mixture. [d] 62% conversion. [e] Performed with 2 (1.5 equiv).

Gratifyingly benzaldehyde 2b (entry 2) smoothly participated to the reaction leading to the desired product 3b in 94% yield, and the same cis:trans selectivity (d.r. 57:43). The aromatic ring substitution in the ortho, meta or para position with electron-withdrawing groups (entries 3-6) is well tolerated as in all the cases the piperidines 3c-f were obtained in 86-97% yields. The reaction proved to be less efficient for aromatic aldehydes substituted with an electron-donating group especially in the para position (entries 7, 10 and 11), leading to the products 3g, j and k in 60%, 60% and 74% yield respectively. It’s interesting to note that in the presence of an ortho substituent on the aromatic ring, the cis-product was obtained as major diastereomer (entries 3, 8 and 9) affording the desired piperidines with up to 87:13 d.r. probably because of the steric hindrance.¹² Aliphatic aldehydes undergo aza-Prins cyclization in high yields (entries 12-14), however in the case of 3- phenylpropionaldehyde (2m) and n-octanal (2n) a slight excess of aldehyde was needed (1.5 equiv) to have a complete conversion of 1; these aldehydes reacting with themselves leading to small amount of the aldol-crotonization products.

The scope of the reaction was then extended to other protected homoallylic amines. Contrarily to the scarce previously reported results,^13,3,10c our reaction conditions are not compatible with the use of carbamates as protecting group on the nitrogen atom. Both the Boc- and Cbz- are cleaved in the presence of the combination of TiCl4 and p-TsOH.H2O and no trace of the aza-Prins product was observed. Otherwise the aza-Prins reaction with homoallylic amine protected by the widely used p- methoxyphenyl (PMP) group 4 was also carried out and the results are reported in Table 3.

Table 3. Scope of the aza-Prins cyclization with PMP-protected homoallylic amine 4.^a

Entry Aldehyde 2 R= Product 5 Yield (%)^[b] Cis/trans (d.r.)^[c]

1 p-Br-C6H4 2a

5a

99 12:88

2 C6H5 2b

5b

93 23:77

3 o-Cl-C6H4 2c

5c

99 28:72

4 p-NO2-C6H4 2e

5d

92 14:86

5 p-OCH3-C6H4 2j _N

Cl

PMP OMe 5e

40^[d] 20:80

6 p-CH3-C6H4 2k

5f

90 22:78

7 (CH3)2CH 2l

5g

98 9:91

[a] General conditions: 4 (1 equiv.), 2 (1 equiv.), TiCl4 (1 equiv.), p-TsOH.H2O (10 mol%), in CH2Cl2

(0.1 M) at 60 °C in a sealed vial 16 h. [b] Yields refer to isolated products. [c] ¹H NMR determination on the crude mixture. [d] 49% conversion.

In the presence of aromatic aldehydes substituted on the ortho or para positions with electron withdrawing groups 2a-c and e the aza-Prins products 5a-d, were isolated in up to 99% yields, this time surprisingly, with a good diastereoselection in favor of the trans isomer (d.r. up to 86:14).

Aliphatic isobutyraldehyde 2l also provided the desired piperidine 5g in very good yield and as single diastereomer (trans:cis = 91:9). The substitution on the aromatic ring with strong electron donating groups is less tolerated. Indeed, while p-tolualdehyde (2k) smoothly reacted to give the desired

piperidine in 90% yield (entry 6), p-anisaldehyde (2j) gave the product in only 40% yield (entry 5) and 2,5-dimethoxy benzaldehyde (2h) did not react at all. This is probably due to electronic effects, since the iminium intermediate is too electron enriched due to the donating PMP and methoxy groups. To illustrate the synthetic utility of this methodology we deprotected the PMP group in standard reaction conditions, in the presence of ceric ammonium nitrate CAN, in order to obtain the NH free piperidine as the single trans 7a diastereomer in 73% yield (Scheme 1), thus with an overall yield of 66% over two steps.

Scheme 1. Deprotection of the PMP group of the piperidine trans 5a.

We next wondered about the possibility to carry out the aza-Prins cyclization with the but-3-en-1- amine (6). Indeed very few examples are reported in the literature using a free homoallyl amine or an imine. To our delight, although the reaction time was longer (90 h instead of overnight) the synergistic combination of TiCl4 with p-TsOH.H2O allowed isolation of the expected piperidines 7 in good yields and gratifyingly as the single cis-stereoisomer (d.r. > 95/5) (Table 4).

Table 4. Scope of the aza-Prins yclization with homoallyl amine 6.^a

Entry Aldehyde 2 R= Product 7 Yield (%)^[b]

1 p-Br-C6H4 2a

7a

77

2 C6H5 2b

7b

86

3 o-Cl-C6H4 2c

7c

80

4 p-NO2-C6H4 2e

7d

82

5 p-OCH3-C6H4 2j _N

H Cl

OMe 7e

34^[c]

6 p-CH3-C6H4 2k

7f

70^[c]

7 (CH3)2CH 2l

7g

88

[a] General conditions: 6 (1 equiv.), 2 (1 equiv.), TiCl4 (1 equiv.), p-TsOH.H2O (10 mol%), in CH2Cl2

(0.1 M) at 60 °C in a sealed vial 90 h. [b] Yields refer to isolated products. [c] Reaction time prolonged to 160 h.

Again the only exception in this trend concerns the electron rich aldehydes; the reaction with 2k afforded the piperidine 7f in 70% yield after a longer reaction time (160 h) and 2j afforded 7g in only 32% yield after 160 h.

The structure of compounds trans 3e and cis 7a and their relative configurations were determined by NOESY experiments¹⁴ and confirmed by single crystal X-ray analysis¹⁴ (Figure 1).

Figure 1 ORTEP representation of the piperidines products trans-3e and cis-7a. The thermal ellipsoids are shown at 50% probability.

It is worth noting that the cis/trans ratio is strongly dependent on the feature of the nitrogen atom substituent, as depicted in Table 5. To determine the trend of the selectivity dependence, the reactions between benzaldehyde (2b) and different substituted homoallylic amines were performed.

Table 5. Selectivity dependence.

Entry R= Product (Yield %)^[a] Cis/trans

(d.r.)^[b]

1 CH2CO2Me (1) 3b (94) 57:43

2 PMP (4) 5b (93) 23:77

3 H (6) 7b (86) >95:5

4 Ts (8) 11 (93) >5:95

5 Bn (9) 12 (66) 50:50

6 n-Pr (10) 13 (90) 50:50

[a] Yields refer to isolated products. [b] ¹H NMR determination on the crude mixture.

HN H

H

H H

H Cl H

H H Br

Noesy

With N-tosyl homoallyl amine (8) only the product trans 11 was recovered in 95% yield (entry 4).

Next we employed N-alkyl homoallylic amines such as N-benzyl (9) and N-propyl (10) (entries 5 and 6): both delivered an equimolar mixture of cis and trans isomers 12 and 13 in good yield. We can therefore conclude that whereas the free amine 6 led to the piperidine cis 7b as unique stereoisomer (entry 3), the arylamine 4 and the tosylamine 8 gave the trans isomer as major product (entries 2 and 4), finally no selectivity was observed with the alkylamines 1, 9 and 10 (entries 1, 5 and 6).

These results could be explained as follow (Figure 2). According to the common reaction mechanism of the aza-Prins cyclization, the reaction starts by the formation of an iminium whose A and B forms are in equilibrium and then the nucleophilic attack (here the chloride anion) occurs on the equatorial position. As mentioned by Padrón et al.,^2a in the case of R¹=Ts, ab-initio calculations showed that the iminium B is more stable than the isomer A. This is probably due to the strong steric repulsion between the groups R¹ and R in comparison to the lower energy cost of the allylic strain between R and H. Obviously, this comment can also explain the trans- selectivity with R¹=PMP. When R¹=H, only the allylic strain remains,¹⁵ favoring thus the formation of the iminium A and consequently the formation of the cis-piperidine. The observed lack of selectivity when the amine bears an alkyl chain (homoallylic amine 1) is certainly due to an equivalent energy cost between the steric repulsion for the iminium A and the allylic strain for B. This last case helps us to better understand the high cis- selectivity when the reaction was carried out with ortho-substituted aryl aldehydes (Table 2, entries 3- 8-9). These ortho-substituents could contribute to increase the steric hindrance detrimental to the iminium B by reinforcing the negative contribution of the allylic strain versus the steric repulsion between the residue CH2CO2Me (R¹) and the aryl group (R).

Figure 2. Comparison of possible transition structures for the cyclization reaction.

In conclusion, we have demonstrated that the synergism between TiCl4 and p-TsOH.H2O can promote the aza-Prins cyclization with N-aryl, -alkyl and even non protected homoallylic amines. The piperidine derivatives are obtained in good yields and with a cis/trans ratio dependent on the group borne by the nitrogen atom. The trans-isomer was obtained as major compound when tosyl and PMP are used as protecting groups, while the cis-isomer was formed in the absence of protecting group.

This methodology can be useful for preparing either cis- or trans- piperidines and could be later used for the synthesis of valuable piperidine scaffolds found in natural and bioactive products.

Experimental section General information

All the reactions were performed in dried glassware, under argon atmosphere and with dry solvents.

Reagents were obtained from commercial suppliers and used without further purification unless otherwise noted. TLC analyses were performed using precoated Merck TLC Silica Gel 60 F254 plates.

Purifications by column chromatography on silica gel were performed using Merck Silica Gel 60 (70- 230 mesh) and purifications by preparative thin layer chromatography on silica gel using Merck Silica Gel 60 PF254. Petroleum ether (PE) used for purifications was the low boiling point fraction (40-60

°C). ¹H NMR and ¹³C spectra were recorded on a 300 Mhz instrument using TMS and CDCl3

respectively as internal standards. Chemical shifts (δ) are reported in parts per million (ppm). The

following abbreviations are used for multiplicities: s, singlet; d, doublet; t, triplet; dd, doublet of doublets; q, quadruplet; quint, quintuplet; td, triplet of doublets; dt, doublet of triplets; tt, triplet of triplets, m, multiplet. Carbon multiplicities were determined by Jmod experiments. Coupling constants (J) are reported in Hertz (Hz). - HRMS analyses were obtained using MaXis 4G or a TOF Q for ESI.

X-ray crystallographic data were collected on a crystal diffractometer. Melting points were obtained on a hot bench.

Preparation of N-methyl but-3-en-1-ylglycinate (1): To a solution of methyl glycinate hydrochloride (11.12 g, 2 equiv., 88.6 mmol) in acetonitrile (220 mL) was added K2CO3 (18.36 g, 3 equiv., 133 mmol). The mixture was stirred 1 h at room temperature, then 4-bromo-1-butene (4.5 mL, 1 equiv., 44.9 mmol) was added and the stirring continued at 45 °C for 48 h. The insoluble material was filtered off and the filtrate concentrated under reduced pressure. CH2Cl2 (60 mL) and H2O were added, the two-phase mixture was separated, and the aqueous phase was extracted twice with CH2Cl2. The combined organic phases were dried over MgSO4, filtered, and evaporated in vacuo. Compound 1 was isolated as colorless oil (6.01 g, 90% yield) after distillation (70 °C, to reduced pressure). ¹H NMR (CDCl3, 300 MHz): δ = 5.85-5.75 (m, 1 H), 5.14-5.04 (m, 2 H), 3.73 (s, 3 H), 3.43 (s, 2 H), 2.68 (t, J = 6.7 Hz, 2 H), 2.26 (q, J = 6.7 Hz, 2 H), 1.66 (bs, NH). ¹³C NMR (CDCl3, 75 MHz): δ = 173.0 (C=O), 136.2 (=CH), 116.7 (=CH2), 51.9 (CH3), 50.8 (CH2), 48.6 (CH2), 34.4 (CH2). ESI-HRMS calculated for C7H14NO2 [M+H]⁺ 144.1024, found 144.1022.

Preparation of N-(but-3-en-1-yl)-4-methoxyaniline (4): To a solution of p-anisidine (6.16 g, 5 equiv., 49.2 mmol) and 4-bromo-1-butene (1.33 g, 1 equiv., 9.85 mmol) in EtOH (20 mL) was added NaI (147 mg, 0.1 equiv., 0.98 mmol). The mixture was stirred to reflux for 4 h, and then the solvent was removed in vacuo. CH2Cl2 (20 mL) followed by KOH (1 M, 20 mL) were added. The two-phase mixture was separated, and the organic phase was washed with water (2 × 20 mL) and brine (2 × 20 mL), dried over MgSO4, filtered, and evaporated in vacuo. The compound 4 was isolated as brown oil (1.58 g, 90% yield) after purification by flash chromatography (10% EtOAc in petroleum ether). ¹H NMR (CDCl3, 300 MHz): δ = 6.78 (d, J = 8.8 Hz 2 H), 6.58 (d, J = 8.8 Hz, 2 H), 5.86-5.75 (m, 1 H), 5.16-5.08 (m, 2 H), 3.73 (s, 3 H), 3.27 (bs, NH), 3.13 (t, J = 6.7 Hz, 2 H), 2.36 (q, J = 6.7 Hz, 2 H).

13C NMR (CDCl3, 75 MHz): δ = 152.2 (C), 142.6 (C), 136.0 (=CH), 117.1 (=CH2), 115.0 (2 × CH), 114.4 (2 × CH), 55.9 (CH3), 43.9 (CH2), 33.8 (CH2). ESI-HRMS calculated for C11H16NO [M+H]⁺ 178.1232, found 178.1232.

Preparation of N-but-3-en-1-yl-4-methylbenzenesulfonamide (8): This substrate was synthesized according to a described procedure.¹⁶ To a solution of 3-buten-1-amine (662 mg, 1 equiv., 9.3 mmol), NEt3 (1.9 mL, 1.5 equiv., 13.9 mmol) and dimethylaminopyridine (341 mg, 0.3 equiv., 2.79 mmol) in CH2Cl2 (30 mL), at 0 °C tosyl chloride (2.13 g, 11.2 mmol, 1.2 eq) was added. The reaction was warmed to r.t., stirred for 3 h, quenched with water and the aqueous layer was extracted three times with CH2Cl2. The combined organic phases were dried over MgSO4, filtered, and evaporated in vacuo.

The residue was purified by flash chromatography (EP/EtOAc 4:1) to afford the corresponding tosylamine 15 (2.08 g, 99% yield) as colourless oil. ¹H NMR (CDCl3, 300 MHz): δ = 7.75 (d, J = 8.4 Hz, 2 H), 7.32 (d, J = 8.4 Hz 2 H), 5.69-5.56 (m, 1 H), 5.09-5.01 (m, 2 H), 4.42 (s, NH), 3.02 (q J = 6.6 Hz, 2 H), 2.43 (s, 3 H), 2.20 (q, J = 6.6 Hz, 2 H). ¹³C NMR (CDCl3, 75 MHz) : δ = 143.6 (C), 137.1 (C), 134.3 (=CH), 129.9 (2 × CH), 127.3 (2 × CH),118.4 (=CH2), 42.2 (CH2), 33.7 (CH2) 21.7 (CH3).

Preparation of N-benzylbut-3-en-1-amine (9): This substrate was synthesized according to a described procedure.¹⁷ To a solution of benzylamine (5.25 g, 5 equiv., 49.0 mmol) and 4-bromo-1- butene (1 mL, 1 equiv., 9.85 mmol) in EtOH (20 mL), NaI (150 mg, 0.1 equiv., 0.98 mmol) was added. The mixture was stirred to reflux for 4 h. Then the solvent was removed in vacuo, CH2Cl2 (20 mL) followed by KOH (1 M, 20 mL) were added and the two-phase mixture was separated. The organic phase was washed with water (2 × 20 mL) and brine (2 × 20 mL), dried over MgSO4, filtered, and evaporated in vacuo. The residue was purified by flash chromatography (10 % EtOAc in petroleum ether) to give pure product 17 (N-benzylbut-3-en-1-amine) as a yellow oil (1.51 g, 95%

yield). ¹H NMR (CDCl3, 300 MHz): δ = 7.33–7.22 (m, 5 H), 5.85-5.72 (m, 1 H), 5.12–5.02 (m, 2 H), 3.81 (s, 2 H), 2.71 (t, J = 6.8 Hz, 2 H), 2.31 (qt, J = 6.8, 1.3 Hz, 2 H), 1.84 (br s, 1 H). ¹³C NMR (CDCl3, 75 MHz): δ = 140.1 (C), 136.5 (=CH), 128.6 (2 × CH), 128.3 (2 × CH), 127.1 (CH), 116.6 (=CH2), 53.9 (CH2), 48.3 (CH2), 34.3 (CH2).

Preparation of N-propylbut-3-en-1-amine (10): To a solution of but-3-en-1-amine (0.77 mL, 1.0 equiv., 8.4 mmol) in MeOH (10 mL) was added propanal (0.74 mL, 1.2 equiv., 10.1 mmol). The mixture was stirred at room temperature for 2 h. Solid NaBH4 (794 mg, 2.5 equiv., 21 mmol) was then added portionwise over 1 h. The reaction was stirred at room temperature overnight, quenched with 2.0 M aq. NaOH (10 mL) and extracted with Et2O (3 × 30 mL). The organic layers were combined, dried over MgSO4, filtered, and evaporated in vacuo. The residue was purified by distillation (70 °C under reduce pressure) to give compound 19 (900 mg, 95% yield) as a colorless oil. ¹H NMR (CDCl3, 300 MHz): δ = 5.86-5.72 (m, 1 H), 5.12–5.02 (m, 2 H), 2.67 (t, J = 6.8 Hz, 2 H), 2.57 (t, J = 7.3 Hz, 2 H), 2.28 (qt, J = 6.8, 1.2 Hz, 2 H), 1.51 (q, J = 7.3 Hz, 2 H), 0.91 (t, J = 7.3 Hz, 3 H). ¹³C NMR (CDCl3, 75 MHz): δ = 136.7 (=CH), 116.4 (=CH2), 51.9 (CH2), 48.9 (CH2), 34.5 (CH2), 23.3 (CH2), 11.9 (CH3).

4-Methoxyphenyl deprotection: To a solution of trans 5a (114.2 mg, 1.0 equiv., 0.3 mmol) in MeCN-H2O (4:1, 6 mL) was added ceric ammonium nitrate Ce(NH4)2(NO3)6 (987 mg, 6 equiv., 1.8 mmol) at 0 °C. The mixture was stirred at the same temperature for 3 h. Solid NaBH4 (794 mg, 2.5 equiv., 21 mmol) was then added portionwise over 1 h. Then water (12 mL) was added and extracted with EtOAc (90 mL). The aqueous layer was basified with K2CO3, filtered through a pad of celite and extracted with EtOAc (2 × 30 mL). The organic layers were combined, dried over MgSO4, filtered, and evaporated in vacuo. The residue was purified by flash chromatography (100% EtOAc) to give pure product trans 7a (60 mg, 73% yield) as a black solid. Black solid, M.p. 78-80 °C ¹H NMR (CDCl3, 300 MHz): δ = 7.45 (d, J = 8.3 Hz, 2 H), 7.26 (d, J = 8.3 Hz, 2 H), 4.60 (quint, J = 3.0 Hz, 1 H), 4.15 (dd, J = 10.7, 3.0 Hz, 1 H), 3.31 (td, J = 12.1, 3.0 Hz, 1 H), 3.08 (bs, NH), 3.01(ddd, J = 12.1, 4.4, 2.6 Hz, 1 H), 2.13-1.91 (m, 4 H). ¹³C NMR (CDCl3, 75 MHz): δ = 142.7 (C), 131.7 (2 × CH), 128.7 (2 × CH), 121.3 (C), 57.9 (CH), 54.8 (CH), 42.0 (CH2), 41.2 (CH2), 33.2 (CH2). ESI-HRMS calculated for C11H14NClBr [M+H]⁺ 273.9993, found 273.9993.

General procedure

To a solution of homoallylic amine (1 equiv., 0.4 mmol) and aldehyde (1 equiv*., 0.4 mmol) in CH2Cl2 (4 mL) p-TSA.H2O (0.1 equiv., 0.04 mmol) was added. The mixture was stirred for 15 min

then a solution of TiCl4 (1 M in CH2Cl2, 1 equiv., 0.4 mmol) was added. The solution was stirred at 60

°C for 16 h (with amine 1, 4, 15, 17 and 19), 90 h (with amine 6**) or 160 h (with amine 8, 10 and 12), quenched with NaHCO3 and extracted with CH2Cl2. The combined organic layers were dried with MgSO4, solvent was removed, and the residue was purified by flash chromatography on silica gel (10% EtOAc in petroleum ether) to give the pure piperidine products.

* 1.5 eq for aldehyde 2m and 2n

** For amine 6 reaction with 2j and 2k has been extended for 160 h

Methyl 2-(2-(4-bromophenyl)-4-chloropiperidin-1-yl)acetate 3a (98%, 136 mg, dr: 57:43)

Cis 3a: Orange oil ¹H NMR (CDCl3, 300 MHz): δ = 7.45 (d, J = 8.4 Hz, 2 H), 7.22 (d, J = 8.4 Hz, 2 H), 3.94 (tt, J = 11.7, 4.3 Hz, 1 H), 3.63 (dd, J = 12.1, 2.2 Hz, 1 H), 3.61 (s, 3 H), 3.08 (ddd, J = 12.1, 4.1, 2.8 Hz, 1 H), 3.07 (ABq, 2 H), 2.66 (td, J = 12.1, 2.2 Hz, 1 H), 2.24-2.15 (m, 2 H), 2.06 (qd, J = 12.1, 4.1 Hz, 1 H), 1.89 (q, J = 12.1 Hz, 1 H). ¹³C NMR (CDCl3, 75 MHz): δ = 171.1 (C), 141.1 (C), 132.1 (2 × C), 129.5 (2 × C), 121.7 (C), 64.9 (C), 56.5 (C), 54.9 (C), 52.4 (C), 51.5 (C), 45.9 (C), 36.8 (C). ESI-HRMS calculated for C14H17NO2ClBrNa [M+Na]⁺ 368.0029, found 368.0032. Trans 3a:

Yellow oil ¹H NMR (CDCl3, 300 MHz): δ = 7.45 (d, J = 8.5 Hz, 2 H), 7.25 (d, J = 8.5 Hz, 2 H), 4.53 (quint, J = 3.0 Hz, 1 H), 3.95 (dd, J = 10, 3.8 Hz, 1 H), 3.64 (s, 3 H), 3.11 (ABq, 2 H), 3.05-2.92 (m, 2 H-H), 2.32-2.21 (m, 1 H), 2.10-1.95 (m, 3 H). ¹³C NMR (CDCl3, 75 MHz): δ = 171.3 (C), 141.6 (C), 132.1 (2 × C), 129.7(2 × C), 121.5 (C), 60.0 (C), 57.0 (C), 56.0 (C), 51.6 (C), 47.4 (C), 43.1 (C), 33.4 (C). ESI-HRMS calculated for C14H17NO2ClBrNa [M+Na]⁺ 368.0028, found 368.0028.

Methyl 2-(4-chloro-2-phenylpiperidin-1-yl)acetate 3b (94%, 100 mg, dr: 57:43) Cis 3b: Yellow oil ¹H NMR (CDCl3, 300 MHz): δ = 7.33-7.26 (m, 5 H), 3.96 (tt, J = 11.7, 4.3 Hz, 1 H), 3.62 (dd, J = 10.9, 2.6 Hz, 1 H), 3.60 (s, 3 H), 3.10 (ddd, J = 11.9, 4.1, 2.9 Hz, 1 H), 3.08 (ABq, 2 H), 2.66 (td, J = 12.0, 2.6 Hz, 1 H), 2.21 (m, 2 H), 2.07 (qd, J = 12.0, 4.2 Hz, 1 H), 1.96 (q, J = 12.0 Hz, 1 H). ¹³C NMR (CDCl3, 75 MHz): δ = 171.3 (C), 142.0 (C), 128.9 (2 × CH), 128.0 (CH), 127.7 (2

× CH), 65.7 (CH), 56.9 (CH), 55.0 (CH2), 52.5 (CH2), 51.4 (CH3), 46.0 (CH2), 36.9 (CH2). ESI-HRMS calculated for C14H18NO2ClNa [M+Na]⁺ 290.0924, found 290.0922. Trans 3b: Yellow oil ¹H NMR (CDCl3, 300 MHz): δ = 7.38-7.25 (m, 5 H), 4.54 (quint, J = 2.9 Hz, 1 H), 3.94 (dd, J = 10.8, 3.0 Hz, 1

H), 3.63 (s, 3 H), 3.11 (ABq, 2 H), 3.01-2.91 (m, 2 H), 2.30-2.28 (m, 1 H), 2.17-1.96 (m, 3 H). ¹³C NMR (CDCl3, 75 MHz): δ = 171.4 (C), 142.4 (C), 128.9 (2 × CH), 127.9 (2 × CH), 127.8 (CH), 60.7 (CH), 57.3 (CH), 56.1 (CH2), 51.5(CH3), 47.5 (CH2), 43.1(CH2), 33.5 (CH2). ESI-HRMS calculated for C14H18NO2ClNa [M+Na]⁺ 290.0924, found 290.0926.

Methyl 2-(4-chloro-2-(2-chlorophenyl)piperidin-1-yl)acetate 3c (86%, 103 mg, dr: 86:14) Cis 3c: Orange oil ¹H NMR (CDCl3, 300 MHz): δ = 7.61 (dd, J = 7.6, 1.7 Hz, 1 H), 7.33 (dd, J = 7.9, 1.3 Hz, 1 H), 7.28 (td, J = 7.6, 1.3 Hz, 1 H), 7.18 (td, J = 7.9, 1.7 Hz, 1 H), 4.10 (dd, J = 11.2, 3.1 Hz, 1 H), 3.97 (tt, J = 11.7, 4.3 Hz, 1 H), 3.63 (s, 3 H), 3.18 (dt, J = 11.8, 3.5 Hz, 1 H), 3.08 (ABq, 2 H), 2.60 (td, J = 12.0, 2.5 Hz, 1 H), 2.32-2.19 (m, 2 H), 2.06 (qd, J = 12.1, 4.1 Hz, 1 H), 1.79 (q, J = 12.1 Hz, 1 H). ¹³C NMR (CDCl3, 75 MHz): δ = 171.1 (C), 139.2 (C), 133.2 (C), 129.8(CH), 128.8 (CH), 128.6 (CH), 127.7 (CH), 61.2 (CH), 56.4 (CH), 55.3 (CH2), 52.8 (CH2), 51.6 (CH3), 44.5 (CH2), 36.7 (CH2). ESI-HRMS calculated for C14H17NO2Cl2Na [M+Na]⁺ 324.0534, found 324.0536. Trans 3c:

Yellow oil ¹H NMR (CDCl3, 300 MHz): δ = 7.62 (dd, J = 7.6, 1.7 Hz, 1 H), 7.33 (dd, J = 7.9, 1.3 Hz, 1 H), 7.26 (td, J = 7.6, 1.3 Hz, 1 H), 7.17 (td, J = 7.9, 1.7 Hz, 1 H), 4.53 (quint, J = 4.5 Hz, 1 H), 4.46 (dd, J = 11.0, 2.9 Hz, 1 H), 3.66 (s, 3 H), 3.09 (ABq, 2 H), 3.01-2.96 (m, 2 H), 2.29-2.22 (m, 1 H), 2.13-2.08 (m, 1 H), 2.02-1.87 (m, 2 H). ¹³C NMR (CDCl3, 75 MHz): δ = 171.4 (C), 139.9 (C), 133.6 (C), 129.9 (CH), 128.9 (CH), 128.5 (CH), 127.6 (CH), 56.8 (CH), 56.4 (CH), 56.4 (CH2), 51.7 (CH3), 47.7 (CH2), 41.7 (CH2), 33.4 (CH2). ESI-HRMS calculated for C14H17NO2Cl2Na [M+Na]⁺ 324.0534, found 324.0535.

Methyl 2-(4-chloro-2-(4-cyanophenyl)piperidin-1-yl)acetate 3d (96%, 112 mg, dr: 42:58)

Cis 3d: Orange oil ¹H NMR (CDCl3, 300 MHz): δ = 7.64 (d, J = 8.3 Hz, 2 H), 7.47 (d, J = 8.3 Hz, 2 H), 3.95 (tt, J = 11.7, 4.2 Hz, 1 H), 3.78 (dd, J = 12.1, 2.4 Hz, 1 H), 3.62 (s, 3 H), 3.10 (ddd, J = 11.9, 3.9, 2.9 Hz, 1 H), 3.06 (ABq, 2 H), 2.70 (td, J = 12.1, 2.3 Hz, 1 H), 2.26-2.16 (m, 2 H), 2.04 (qd, J = 12.1, 4.2 Hz, 1 H), 1.86 (q, J = 11.7 Hz, 1 H). ¹³C NMR (CDCl3, 75 MHz): δ = 170.8 (C), 147.6 (C), 132.8 (2 × CH), 128.5 (2 × CH), 118.7 (C), 111.8 (C), 65.0 (CH), 56.2 (CH), 54.8 (CH2), 52.2 (CH2), 51.5 (CH3), 45.7 (CH2), 36.6 (CH2). ESI-HRMS calculated for C15H17N2O2ClNa [M+Na]⁺ 315.0876, found 315.0877. Trans 3d: Orange oil ¹H NMR (CDCl3, 300 MHz): δ = 7.64 (d, J = 8.6 Hz, 2 H), 7.51

(d, J = 8.6 Hz, 2 H), 4.53 (quint, J = 2.9 Hz, 1 H), 4.07 (t, J = 6.8 Hz, 1 H), 3.65 (s, 3 H), 3.07 (ABq, 2 H), 3.02 (td, J = 11.6, 3.0 Hz, 1 H), 2.98-2.93 (m, 1 H), 2.27-2.22 (m, 1 H), 2.02-1.98 (m, 3 H). ¹³C NMR (CDCl3, 75 MHz): δ = 171.0 (C), 148.3 (C), 132.7 (2 × CH), 128.6 (2 × CH), 117.7 (C), 111.6 (C), 60.1 (CH), 56.5 (CH), 56.0 (CH2), 51.6 (CH3), 47.1 (CH2), 43.0 (CH2), 33.2 (CH2). ESI-HRMS calculated for C15H17N2O2ClNa [M+Na]⁺ 315.0876, found 315.0876.

Methyl 2-(4-chloro-2-(4-nitrophenyl)piperidin-1-yl)acetate 3e (90%, 111 mg, dr: 38:62)

Cis 3e: Orange oil ¹H NMR (CDCl3, 300 MHz): δ = 8.20 (d, J = 8.8 Hz, 2 H), 7.53 (d, J = 8.6 Hz, 2 H), 3.96 (tt, J = 11.7, 4.3 Hz, 1 H), 3.86 (dd, J = 11.4, 2.5 Hz, 1 H), 3.62 (s, 3 H), 3.11 (ddd, J = 11.9, 4.1, 3.0 Hz, 1 H), 3.07 (ABq, 2 H), 2.72 (td, J = 12.2, 2.5 Hz, 1 H), 2.28-2.17 (m, 2 H), 2.07 (qd, J = 12.2, 4.1 Hz, 1 H), 1.88 (q, J = 11.9 Hz, 1 H). ¹³C NMR (CDCl3, 75 MHz): δ = 170.8 (C), 149.6 (C), 147.7 (C), 128.6 (2 × CH), 124.3 (2 × CH), 64.7 (CH), 56.1 (CH), 54.8 (CH2), 52.2 (CH2), 51.6 (CH3), 45.8 (CH2), 36.7 (CH2). ESI-HRMS calculated for C14H17N2O4ClNa [M+Na]⁺ 335.0775, found 335.0775. Trans 3e: Orange solid M.p. 112-114 °C. ¹H NMR (CDCl3, 300 MHz): δ = 8.20 (d, J = 8.8 Hz, 2 H), 7.59 (d, J = 8.6 Hz, 2 H), 4.54 (quint, J = 3.0 Hz, 1 H), 4.15 (t, J = 7.0 Hz, 1 H), 3.65 (s, 3 H), 3.08 (ABq, 2 H), 3.05-2.94 (m, 2 H), 2.28-2.22 (m, 1 H), 2.04-2.00 (m, 3 H). ¹³C NMR (CDCl3, 75 MHz): δ = 171.0 (C), 150.4 (C), 147.6 (C), 128.7 (2 × CH), 124.2 (2 × CH), 59.9 (CH), 56.5 (CH), 56.0 (CH2), 51.6 (CH3), 47.1 (CH2), 43.1 (CH2), 33.2 (CH2). ESI-HRMS calculated for C14H17N2O4ClNa [M+Na]⁺ 335.0775, found 335.0775.

Methyl 2-(4-chloro-2-(3-nitrophenyl)piperidin-1-yl)acetate 3f (97%, 122 mg, dr: 45:55)

Cis 3f: Yellow solid M.p. 98-100 °C. ¹H NMR (CDCl3, 300 MHz): δ = 8.21 (s, 1 H), 8.15 (d, J = 8.1 Hz, 1 H), 7.71 (d, J = 7.6 Hz, 1 H), 7.53 (t, J = 7.9 Hz, 1 H), 3.97 (tt, J = 11.7, 4.3 Hz, 1 H), 3.86 (dd, J = 11.4, 2.3 Hz, 1 H), 3.62 (s, 3 H), 3.11 (ddd, J = 11.7, 3.9, 2.6 Hz, 1 H), 3.09 (ABq, 2 H), 2.72 (td, J

= 12.2, 2.3 Hz, 1 H), 2.26-2.22 (m, 2 H), 2.06 (qd, J = 12.2, 4.1 Hz, 1 H), 1.90 (q, J = 11.9 Hz, 1 H).

13C NMR (CDCl3, 75 MHz): δ = 170.8 (C), 148.7 (C), 144.4 (C), 133.8 (CH), 130.0 (CH), 123.1 (CH), 122.8 (CH), 64.5 (CH), 56.1 (CH), 54.8 (CH2), 52.2 (CH2), 51.5 (CH3), 46.0 (CH2), 36.7 (CH2). ESI- HRMS calculated for C14H17N2O4ClNa [M+Na]⁺ 335.0775, found 335.0777. Trans 3f: Orange oil ¹H NMR (CDCl3, 300 MHz): δ = 8.26 (t, J = 1.1 Hz, 1 H), 8.14 (qd, J = 8.1 , 1.1 Hz, 1 H), 7.75 (d, J = 7.7

Hz, 1 H), 7.52 (d, J = 7.9 Hz, 1 H), 4.55 (quint, J = 2.9 Hz, 1 H), 4.17 (t, J = 7.0 Hz, 1 H), 3.65 (s, 3 H), 3.09 (dt, J = 11.9, 2.5 Hz, 1 H), 3.08 (ABq, 2 H), 2.98-2.92 (m, 1 H), 2.33-2.23(m, 1 H), 2.07-2.03 (m, 3 H). ¹³C NMR (CDCl3, 75 MHz): δ = 170.9 (C), 148.7 (C), 145.0 (C), 134.1 (CH), 129.9 (CH), 129.9 (CH), 122.9 (CH), 59.7 (CH), 56.6 (CH), 56.0 (CH2), 51.6 (CH3), 47.1 (CH2), 43.2 (CH2), 33.3 (CH2). ESI-HRMS calculated for C14H17N2O4ClNa [M+Na]⁺ 335.0775, found 335.0775.

Methyl 2-(4-chloro-2-(4-(dimethylamino)phenyl)piperidin-1-yl)acetate 3g (60%, 75 mg, dr: 50:50) Cis 3g: White solid M.p. 88-90 °C. ¹H NMR (CDCl3, 300 MHz): δ = 7.17 (d, J = 8.7 Hz, 2 H), 6.68 (d, J = 8.7 Hz, 2 H), 3.95 (tt, J = 11.7, 4.4 Hz, 1 H), 3.60 (s, 3 H), 3.48 (dd, J = 11.4, 2.4 Hz, 1 H), 3.10 (ABq, 2 H), 3.09 (dt, J = 11.8, 3.4 Hz, 1 H), 2.94 (s, 6 H), 2.61 (td, J = 12.0, 2.4 Hz, 1 H), 2.22- 2.17 (m, 2 H), 2.12-1.93 (m, 2 H). ¹³C NMR (CDCl3, 75 MHz): δ = 171.5 (C), 150.3 (C), 129.5 (C), 128.5 (2 × CH), 112.7 (2 × CH), 65.2 (CH), 57.2 (CH), 54.9 (CH2), 52.5 (CH2), 51.3 (CH3), 45.8 (CH2), 40.7 (2 × CH3), 36.9 (CH2). ESI-HRMS calculated for C16H23N2O2ClNa [M+Na]⁺ 333.1346, found 333.1345. Trans 3g: Brown solid M.p. 60-62 °C. ¹H NMR (CDCl3, 300 MHz): δ = 7.20 (d, J = 8.8 Hz, 2 H), 6.68 (d, J = 8.8 Hz, 2 H), 4.54 (quint, J = 2.9 Hz, 1 H), 3.80 (dd, J = 10.9, 2.8 Hz, 1 H), 3.62 (s, 3 H), 3.11 (ABq, 2 H), 2.94-2.89 (m, 8 H), 2.32-2.22 (m, 1 H), 2.17-2.08 (m, 1 H), 2.02-1.93 (m, 2 H). ¹³C NMR (CDCl3, 75 MHz): δ = 171.7 (C), 150.2 (C), 129.9 (C), 128.7 (2 × CH), 112.7 (2 × CH), 60.0 (CH), 57.8 (CH), 56.1 (CH2), 51.4 (CH3), 47.6 (CH2), 42.9 (CH2), 40.7 (2 × CH3), 33.6 (CH2). ESI-HRMS calculated for C16H23N2O2ClNa [M+Na]⁺ 333.1346, found 333.1348.

Methyl 2-(4-chloro-2-(2,5-dimethoxyphenyl)piperidin-1-yl)acetate 3h (92%, 120 mg, dr: 87:13) Cis 3h: Yellow solid M.p. 78-80 °C. ¹H NMR (CDCl3, 300 MHz): δ = 7.10 (d, J = 2.85 Hz, 1 H), 6.81-6.73 (m, 2 H), 3.98-3.92 (m, 2 H), 3.77 (s, 3 H), 3.76 (s, 3 H), 3.62 (s, 3 H), 3.16 (dt, J = 11.7, 3.5 Hz, 1 H), 3.07 (ABq, 2 H), 2.52 (td, J = 12.0, 2.0 Hz, 1 H), 2.26-2.17 (m, 2 H), 2.08 (qd, J = 12.0, 4.0 Hz, 1 H), 1.87 (q, J = 12.0 Hz, 1 H). ¹³C NMR (CDCl3, 75 MHz): δ = 171.4 (C), 154.3 (C), 151.0 (C), 130.9 (C), 113.9 (CH), 112.9 (CH), 112.2 (CH), 58.1 (CH), 56.9 (CH), 56.1(CH3), 55.8 (CH3), 55.6 (CH2), 53.2 (CH2), 51.5 (CH3), 44.6 (CH), 36.7 (CH). ESI-HRMS calculated for C16H22NO4ClNa [M+Na]⁺ 350.1135, found 350.1139. Trans 3h: Yellow solid M.p. 72-74 °C. ¹H NMR (CDCl3, 300 MHz): δ = 7.11 (d, J = 3.00 Hz, 1 H), 6.81-6.75 (m, 2 H), 4.53 (quint, J = 2.9 Hz, 1 H), 4.32 (dd, J =

7.7, 5.9 Hz, 1 H), 3.78 (s, 3 H), 3.76 (s, 3 H), 3.64 (s, 3 H), 3.10 (ABq, 2 H), 2.99-2.86 (m, 2 H), 2.29- 2.24 (m, 1 H), 2.03-2.01 (m, 3 H). ¹³C NMR (CDCl3, 75 MHz): δ = 171.8 (C), 154.3 (C), 151.5 (C), 131.6 (C), 113.7 (CH), 113.1 (CH), 112.5 (CH), 57.5 (CH), 56.6 (CH2), 56.5 (CH), 55.9 (CH3), 53.0 (CH3), 51.6 (CH3), 48.1 (CH2), 41.7 (CH2), 33.5 (CH2). ESI-HRMS calculated for C16H22NO4ClNa [M+Na]⁺ 350.1135, found 350.1144.

Methyl 2-(4-chloro-2-(2-methoxyphenyl)piperidin-1-yl)acetate 3i (65%, 78 mg, dr: 85:15)

Cis 3i: Orange oil ¹H NMR (CDCl3, 300 MHz): δ = 7.50 (dd, J = 7.5, 1.7 Hz, 1 H), 7.22 (ddd, J = 8.2, 7.5, 1.7 Hz, 1 H), 6.97 (td, J = 8.2, 1.0 Hz, 1 H), 6.85 (dd, J = 8.2, 1.0 Hz, 1 H), 4.00-3.95 (m, 2 H), 3.80 (s, 3 H), 3.61 (s, 3 H), 3.18 (dt, J = 11.8, 3.4 Hz, 1 H), 3.06 (Abq, 2 H), 2.52 (td, J = 12.0, 2.5 Hz, 1 H), 2.23-2.13 (m, 2 H), 2.08 (qd, J = 12.1, 4.0 Hz, 1 H), 1.89 (q, J = 12.1 Hz, 1 H). ¹³C NMR (CDCl3, 75 MHz): δ = 171.5 (C), 156.8 (C), 129.8 (C), 128.4 (CH), 128.0 (CH), 121.2 (CH), 110.7 (CH), 57.9 (CH), 57.0 (CH), 55.6 (CH2), 55.5 (CH3), 53.2 (CH2), 51.5 (CH3), 44.6 (CH2), 36.8 (CH2).

ESI-HRMS calculated for C15H21NO3Cl [M+H]⁺ 298.1210 , found 298.1211. Trans 3i: Orange oil ¹H NMR (CDCl3, 300 MHz): δ = 7.50 (dd, J = 7.5, 1.7 Hz, 1 H), 7.22 (ddd, J = 8.2, 7.5, 1.7 Hz, 1 H), 6.95 (td, J = 8.2, 1.0 Hz, 1 H), 6.86 (dd, J = 8.2, 1.0 Hz, 1 H), 4.54 (quint, J = 2.8 Hz, 1 H), 4.35 (m, 1 H), 3.82 (s, 3 H), 3.63 (s, 3 H), 3.09 (ABq, 2 H), 3.02-2.86 (m, 2 H), 2.34-2.26 (m, 1 H), 2.06-1.95 (m, 3 H). ¹³C NMR (CDCl3, 75 MHz): δ = 171.7 (C), 157.3 (C), 130.3 (C), 128.3 (CH), 128.3 (CH), 121.2 (CH), 110.8 (CH), 57.5 (CH), 56.5 (CH2), 55.7 (CH3), 52.8 (CH), 51.6 (CH3), 48.2 (CH2), 41.5 (CH2), 33.5 (CH2). ESI-HRMS calculated for C15H21NO3Cl [M+H]⁺ 298.1210 , found 298.1209.

Methyl 2-(4-chloro-2-(4-methoxyphenyl)piperidin-1-yl)acetate 3j (60%, 71 mg, dr: 62:38)

Cis 3j: Orange oil ¹H NMR (CDCl3, 300 MHz): δ = 7.23 (d, J = 8.6 Hz, 2 H), 6.85 (d, J = 8.6 Hz, 2 H), 3.95 (tt, J = 11.8, 4.3 Hz, 1 H), 3.80 (s, 3 H), 3.60 (s, 3 H), 3.56 (dd, J = 11.3, 2.3 Hz, 1 H), 3.09 (dt, J = 11.7, 3.4 Hz, 1 H), 3.08 (ABq, 2 H), 2.67 (td, J = 12.1, 2.4 Hz, 1 H), 2.22-2.17 (m, 2 H), 2.05 (qd, J = 12.1, 4.2 Hz, 1 H), 1.95 (q, J = 12.1 Hz, 1 H). ¹³C NMR (CDCl3, 75 MHz): δ = 171.4 (C), 159.3 (C), 134.0 (C), 128.8 (2 × CH), 114.2 (2 × CH), 65.0 (CH), 57.0 (CH), 55.4 (CH3), 54.9 (CH2), 52.5 (CH2), 51.4 (CH3), 46.0 (CH2), 36.9 (CH2). ESI-HRMS calculated for C15H20NO3ClNa [M+Na]⁺ 320.1029, found 320.1028. Trans 3j: Orange oil ¹H NMR (CDCl3, 300 MHz): δ = 7.27 (d, J = 8.7 Hz,

2 H), 6.86 (d, J = 8.7 Hz, 2 H), 4.54 (quint, J = 3.0 Hz, 1 H), 3.87 (dd, J = 11.0, 2.4 Hz, 1 H), 3.79 (s, 3 H), 3.63 (s, 3 H), 3.10 (ABq, 2 H), 2.98-2.94 (m, 2 H), 2.32-2.21 (m, 1 H), 2.15-1.94 (m, 3 H). ¹³C NMR (CDCl3, 75 MHz): δ = 171.6 (C), 159.2 (C), 134.4 (C), 129.0 (2 × CH), 114.2 (2 × CH), 59.9 (CH), 57.6 (CH), 56.1 (CH2), 55.4 (CH3), 51.5 (CH3), 47.6 (CH2), 43.1 (CH2), 33.6 (CH2). ESI-HRMS calculated for C15H20NO3ClNa [M+Na]⁺ 320.1029, found 320.1027.

Methyl 2-(4-chloro-2-p-tolylpiperidin-1-yl)acetate 3k (74%, 83 mg, dr: 62:38)

Cis 3k: Orange oil ¹H NMR (CDCl3, 300 MHz): δ = 7.23 (d, J = 7.9 Hz, 2 H), 7.15 (d, J = 7.9 Hz, 2 H), 3.94 (tt, J = 11.7, 4.4 Hz, 1 H), 3.61 (s, 3 H), 3.60 (d, J = 7.7 Hz, 1 H), 3.12 (dt, J = 11.8, 3.4 Hz, 1 H), 3.10 (ABq, 2 H), 2.67 (td, J = 12.0, 2.1 Hz, 1 H), 2.34 (s, 3 H), 2.25-2.18 (m, 2 H), 2.09 (qd, J = 11.9, 4.0 Hz, 1 H), 2.00 (q, J = 12.1 Hz, 1 H). ¹³C NMR (CDCl3, 75 MHz): δ = 171.3 (C), 138.8 (C), 137.7 (C), 129.6 (2 × CH), 127.6 (2 × CH), 65.4 (CH), 56.9 (CH), 54.9 (CH2), 52.5 (CH2), 51.4 (CH3), 45.9 (CH2), 36.8 (CH2), 21.2 (CH3). ESI-HRMS calculated for C15H21NO2Cl [M+H]⁺ 282.1261 , found 282.1264. Trans 3k: Orange oil ¹H NMR (CDCl3, 300 MHz): δ = 7.24 (d, J = 7.9 Hz, 2 H), 7.13 (d, J

= 7.9 Hz, 2 H), 4.54 (quint, J = 2.9 Hz, 1 H), 3.87 (dd, J = 10.8, 2.9 Hz, 1 H), 3.63 (s, 3 H), 3.11 (ABq, 2 H), 2.95-2.90 (m, 2 H), 2.32 (s, 3 H), 2.29-2.21 (m, 1 H), 2.15-2.06 (m, 1 H), 2.02-1.95 (m, 2 H). ¹³C NMR (CDCl3, 75 MHz): δ = 171.6 (C), 139.5 (C), 137.4 (C), 129.5 (2 × CH), 127.8 (2 × CH), 60.3 (CH), 57.5 (CH), 56.2 (CH2), 51.5 (CH3), 47.5 (CH2), 43.1 (CH2), 33.5 (CH2), 21.2 (CH3). ESI-HRMS calculated for C15H21NO2Cl [M+H]⁺ 282.1261 , found 282.1264.

Methyl 2-(4-chloro-2-isopropylpiperidin-1-yl)acetate 3l (86%, 80 mg, dr: 43:57)

Cis 3l: Yellow oil ¹H NMR (CDCl3, 300 MHz): δ = 3.87 (tt, J = 11.8, 4.3 Hz, 1 H), 3.69 (s, 3 H), 3.41 (ABq, 2 H), 2.91 (ddd, J = 12.0, 4.6, 2.5 Hz, 1 H), 2.77 (td, J = 12.1, 2.6 Hz, 1 H), 2.55 (ddd, J = 11.4, 3.9, 2.0 Hz, 1H), 2.11-2.01 (m, 2 H), 1.96-1.79 (m, 2 H), 1.50 (q, J = 11.9 Hz, 1 H), 0.91 (d, J = 6.8 Hz, 3 H), 0.85 (d, J = 6.8 Hz, 3 H). ¹³C NMR (CDCl3, 75 MHz): δ = 171.6 (C), 63.4 (CH), 58.4 (CH), 53.1 (CH2), 52.9 (CH2), 51.5 (CH3), 36.6 (CH2), 35.5 (CH2), 27.9 (CH), 20.0 (CH3), 15.2 (CH3). ESI- HRMS calculated for C11H21NO2Cl [M+H]⁺ 234.1261, found 234.1263. Trans 3l: Yellow oil ¹H NMR (CDCl3, 300 MHz): δ = 4.50 (quint, J = 3.6 Hz, 1 H), 3.72 (s, 3 H), 3.42 (ABq, 2 H), 3.09 (td, J = 11.8, 2.8 Hz, 1 H), 2.85 (ddd, J = 9.8, 4.9, 3.0 Hz, 1 H), 2.76 (dt, J = 12.0, 4.1 Hz, 1 H), 2.05-1.97 (m,

2 H), 1.87-1.81 (m, 2 H), 1.76 (qd, J = 9.8, 3.4 Hz, 1 H), 0.90 (d, J = 6.8 Hz, 3 H), 0.84 (d, J = 6.8 Hz, 3 H). ¹³C NMR (CDCl3, 75 MHz): δ = 171.9 (C), 58.9 (CH), 57.9 (CH), 54.3 (CH2), 51.6 (CH3), 47.9 (CH2), 33.1 (CH2), 32.1 (CH2), 27.3 (CH), 19.9 (CH3), 15.9 (CH3). ESI-HRMS calculated for C11H21NO2Cl [M+H]⁺ 234.1261, found 234.1259.

Methyl 2-(4-chloro-2-phenethylpiperidin-1-yl)acetate 3m (52%, 61 mg, dr: 62:38)

Cis 3m: Orange oil ¹H NMR (CDCl3, 300 MHz): δ = 7.31-7.26 (m, 2 H), 7.21-7.16 (m, 3 H) 3.89 (tt, J

= 11.7, 4.4 Hz, 1 H), 3.68 (s, 3 H), 3.42 (ABq, 2 H), 2.96 (ddd, J = 12.2, 4.2, 2.9 Hz, 1 H), 2.77-2.52 (m, 4 H), 2.22 (dquint, J = 12.6, 2.2 Hz, 1 H), 2.09 (dsex, J = 12.6, 2.2 Hz, 1 H), 1.93-1.86 (m, 2 H), 1.77-1.65 (m, 2 H). ¹³C NMR (CDCl3, 75 MHz): δ = 171.4 (C), 142.0 (C), 128.6 (2 × CH), 128.4 (2 × CH), 126.1 (CH), 58.5 (CH), 57.5 (CH), 53.2 (CH2), 52.9 (CH2), 51.6 (CH3), 41.3 (CH2), 36.2 (CH2), 34.9 (CH2), 31.0 (CH2). ESI-HRMS calculated for C16H23NO2Cl [M+H]⁺ 296.1417 , found 296.1425.

Trans 3m: Orange oil ¹H NMR (CDCl3, 300 MHz): δ = 7.31-7.26 (m, 2 H), 7.21-7.16 (m, 3 H), 4.43 (quint, J = 4.2 Hz, 1 H), 3.70 (s, 3 H), 3.40 (ABq, 2 H), 3.06-2.95 (m, 2 H), 2.80-2.56 (m, 3 H), 2.09- 2.02 (m, 2 H), 1.97-1.89 (m, 3 H), 1.77-1.70 (m, 1 H). ¹³C NMR (CDCl3, 75 MHz): δ = 171.6 (C), 142.1 (C), 128.6 (2 × CH), 128.5 (2 × CH), 126.0 (CH), 57.0 (CH), 54.8 (CH), 54.8 (CH2), 51.8 (CH3), 47.8 (CH2), 38.1 (CH2), 33.5 (CH2), 33.0 (CH2), 31.6 (CH2). ESI-HRMS calculated for C16H23NO2Cl [M+H]⁺ 296.1417 , found 296.1414.

Methyl 2-(4-chloro-2-heptylpiperidin-1-yl)acetate 3n (78%, 90 mg, dr: 62:38)

Cis 3n: Orange oil ¹H NMR (CDCl3, 300 MHz): δ = 3.88 (tt, J = 11.7, 4.3 Hz, 1 H), 3.70 (s, 3 H), 3.41 (s, 2 H), 2.94 (dt, J = 12.1, 3.0 Hz, 1 H), 2.69 (ddd, J = 12.1, 4.2, 2.8 Hz, 1 H), 2.66-2.62 (m, 1 H), 2.18-2.04 (m, 2 H), 1.89 (qd, J = 12.2, 4.3 Hz, 1 H), 1.60 (q, J = 11.9 Hz, 1 H), 1.26 (s, 12 H), 0.88 (t, J = 6.6 Hz, 3H). ¹³C NMR (CDCl3, 75 MHz): δ = 171.5 (C), 59.1 (CH), 57.7 (CH), 53.4 (CH2), 53.0 (CH2), 51.6 (CH3), 41.4 (CH2), 36.3 (CH2), 33.2 (CH2), 31.9 (CH2), 30.0 (CH2), 29.3 (CH2), 24.9 (CH2), 22.8 (CH2), 14.2 (CH3). ESI-HRMS calculated for C15H28NO2ClNa [M+Na]⁺ 312.1706, found 312.1714. Trans 3n: Orange oil ¹H NMR (CDCl3, 300 MHz): δ = 4.42 (quint, J = 4.0 Hz, 1 H), 3.73 (s, 3 H), 3.42 (ABq, 2 H), 3.05-2.98 (m, 2 H), 2.77 (dt, J = 11.9, 4.3 Hz, 1H), 2.11-2.07 (m, 1 H), 1.96- 1.85 (m, 3 H), 1.26 (s, 12 H), 0.88 (t, J = 6.6 Hz, 3H). ¹³C NMR (CDCl3, 75 MHz): δ = 171.5 (C), 57.1

(CH), 55.1 (CH), 54.8 (CH2), 51.8 (CH3), 47.8 (CH2), 38.2 (CH2), 33.6 (CH2), 31.9 (CH2), 31.2 (CH2), 30.0 (CH2), 29.4 (CH2), 25.5 (CH2), 22.8 (CH2), 14.2 (CH3). ESI-HRMS calculated for C15H28NO2ClNa [M+Na]⁺ 312.1706, found 312.1706.

2-(4-bromophenyl)-4-chloro-1-(4-methoxyphenyl)piperidine 5a (99%, 151 mg, dr: 12:88)

Cis 5a: Orange oil ¹H NMR (CDCl3, 300 MHz): δ = 7.27 (d, J = 8.9 Hz, 2 H), 7.10 (d, J = 8.9 Hz, 2 H), 6.86 (d, J = 8.3 Hz, 2 H), 6.64 (d, J = 8.3 Hz, 2 H), 4.02 (tt, J = 11.7, 4.3 Hz, 1 H), 3.91 (dd, J = 11.1, 2.6 Hz, 1 H), 3.67 (s, 3 H), 3.36 (dt, J = 12.4, 3.6 Hz, 1 H), 2.79 (td, J = 12.1, 3.0 Hz, 1 H), 2.37- 2.18 (m, 2 H), 2.17 (qd, J = 12.1, 4.1 Hz, 1 H), 1.96 (q, J = 12.1 Hz, 1 H). ¹³C NMR (CDCl3, 75 MHz): δ = 156.0 (C), 144.5 (C), 142.2 (C), 131.5 (2 × CH), 129.3 (2 × CH), 125.7 (2 × CH), 120.5 (C), 114.0 (2 × CH), 64.6 (CH), 57.5 (CH2), 56.8 (CH), 55.3 (CH3), 46.9 (CH2), 37.5 (CH2). ESI- HRMS calculated for C18H20NOClBr [M+H]⁺ 380.0417 , found 380.0418. Trans 5a: Black solid M.p.

106-108 °C. ¹H NMR (CDCl3, 300 MHz): δ = 7.29 (d, J = 8.5 Hz, 2 H), 7.13 (d, J = 8.5 Hz, 2 H), 6.92 (d, J = 9.0 Hz, 2 H), 6.68 (d, J = 9.0 Hz, 2 H), 4.51-4.47 (m, 2 H), 3.70 (s, 3 H), 3.35 (td, J = 10.9, 2.8 Hz, 1 H), 3.16 (dt, J = 12.3, 4.1 Hz, 1 H), 2.36-2.26 (m, 1 H), 2.17-2.14 (m, 2 H), 2.03 (dd, J = 14.0, 3.0 Hz, 1 H). ¹³C NMR (CDCl3, 75 MHz): δ = 155.4 (C), 145.2 (C), 142.3 (C), 131.5 (2 × CH), 129.4 (2 × CH), 124.4 (2 × CH), 120.4 (C), 114.1 (2 × CH), 58.7 (CH), 56.9 (CH), 55.4 (CH3), 50.7 (CH2), 43.4 (CH2), 34.5 (CH2). ESI-HRMS calculated for C18H20NOClBr [M+H]⁺ 380.0417 , found 380.0416.

4-chloro-1-(4-methoxyphenyl)-2-phenylpiperidine 5b (93%, 113 mg, dr: 23:77)

Cis 5b: Yellow solid M.p. 78-80 °C. ¹H NMR (CDCl3, 300 MHz): δ = 7.26-7.06 (m, 5 H), 6.89 (d, J = 9.0 Hz, 2 H), 6.63 (d, J = 9.0 Hz, 2 H), 4.01 (tt, J = 11.4, 4.5 Hz, 1 H), 3.93 (dd, J = 11.1, 2.7 Hz, 1 H), 3.65 (s, 3 H), 3.39 (dt, J = 12.4, 3.5 Hz, 1 H), 2.81 (td, J = 12.1, 3.1 Hz, 1 H), 2.40-2.34 (m, 1 H), 2.25-2.16 (m, 2 H), 2.02 (q, J = 11.9 Hz, 1 H). ¹³C NMR (CDCl3, 75 MHz): δ = 155.8 (C), 144.9 (C), 143.1 (C), 128.3 (2 × CH), 127.6 (2 × CH), 126.9 (CH), 125.7 (2 × CH), 113.9 (2 × CH), 65.3 (CH), 57.6 (CH2), 57.1 (CH), 55.3 (CH3), 47.1 (CH2), 37.6 (CH2). ESI-HRMS calculated for C18H21NOCl [M+H]⁺ 302.1306, found 302.1305. Trans 5b: Orange oil ¹H NMR (CDCl3, 300 MHz): δ = 7.27-7.08 (m, 5 H), 6.92 (d, J = 9.0 Hz, 2 H), 6.67 (d, J = 9.0 Hz, 2 H), 4.57 (dd, J = 8.5, 3.9 Hz , 1 H), 4.46 (quint, J = 4.1 Hz , 1 H), 3.66 (s, 3 H), 3.39 (td, J = 11.3, 2.9 Hz, 1 H), 3.18 (dt, J = 12.6, 4.4 Hz, 1 H),

2.35-2.14 (m, 3 H), 2.06-1.99 (m, 1 H). ¹³C NMR (CDCl3, 75 MHz): δ = 154.9 (C), 145.4 (C), 142.8 (C), 128.4 (2 × CH), 127.6 (2 × CH), 126.7 (C), 123.6 (2 × CH), 114.1 (2 × CH), 59.2 (CH), 57.0 (CH), 55.4 (CH3), 50.1 (CH2), 43.1 (CH2), 34.6 (CH2). ESI-HRMS calculated for C18H21NOCl [M+H]⁺ 302.1306, found 302.1306.

4-chloro-2-(2-chlorophenyl)-1-(4-methoxyphenyl)piperidine 5c (99%, 130 mg, dr: 28:72)

Cis 5c: Yellow oil ¹H NMR (CDCl3, 300 MHz): δ = 7.45-7.41 (m, 1 H), 7.23-7.20 (m, 1 H), 7.04-6.95 (m, 2 H), 6.87 (d, J = 9.0 Hz, 2 H), 6.65 (d, J = 9.0 Hz, 2 H), 4.50 (dd, J = 11.0, 2.7 Hz, 1 H), 4.06 (tt, J = 11.6, 4.5 Hz, 1 H), 3.67 (s, 3 H), 3.45 (dt, J = 12.4, 3.6 Hz, 1 H), 2.79 (td, J = 12.2, 3.0 Hz, 1 H), 2.48-2.43 (m, 1 H), 2.27-2.24 (m, 1 H), 2.19 (qd, J = 12.0, 4.2 Hz, 1 H), 1.85 (q, J = 12.0 Hz, 1 H). ¹³C NMR (CDCl3, 75 MHz): δ = 155.8 (C), 144.8 (C), 140.1 (C), 132.2 (C), 129.3 (CH), 129.2 (CH), 127.9 (CH), 127.2 (CH), 124.9 (2 × CH), 114.1 (2 × CH), 59.7 (CH), 58.0 (CH2), 56.8 (CH), 55.3 (CH3), 44.8 (CH2), 37.6 (CH2). ESI-HRMS calculated for C18H20NOCl2 [M+H]⁺ 336.0922 , found 336.0923. Trans 5c: Yellow solid M.p. 96-98 °C. ¹H NMR (CDCl3, 300 MHz): δ = 7.42-7.38 (m, 1 H), 7.23-7.20 (m, 1 H), 7.01-6.97 (m, 2 H), 6.92 (d, J = 9.0 Hz, 2 H), 6.66 (d, J = 9.0 Hz, 2 H), 5.00 (dd, J = 10.4, 2.9 Hz, 1 H), 4.55 (quint, J = 3.2 Hz, 1 H), 3.65 (s, 3 H), 3.32-3.26 (m, 2 H), 2.37-2.23 (m, 2 H), 2.08-1.92 (m, 2 H). ¹³C NMR (CDCl3, 75 MHz): δ = 155.5 (C), 145.5 (C), 140.7 (C), 132.5 (C), 129.3 (CH), 129.3 (CH), 127.7 (CH), 127.0 (CH), 124.5 (2 × CH), 114.1 (2 × CH), 56.9 (CH), 55.3 (CH3), 54.3 (CH), 52.1 (CH2), 41.9 (CH2), 34.4 (CH2). ESI-HRMS calculated for C18H20NOCl2

[M+H]⁺ 336.0922 ,found 336.0919.

4-chloro-1-(4-methoxyphenyl)-2-(4-nitrophenyl)piperidine 5d (92%, 131 mg, dr: 14:86)

Trans 5d: Black solid M.p. 106-108 °C. ¹H NMR (CDCl3, 300 MHz): δ = 8.02 (d, J = 8.7 Hz, 2 H), 7.45 (d, J = 8.7 Hz, 2 H), 6.94 (d, J = 8.9 Hz, 2 H), 6.68 (d, J = 8.9 Hz, 2 H), 4.62 (dd, J = 9.6, 3.7 Hz, 1 H), 4.56 (quint, J = 3.3 Hz, 1 H), 3.68 (s, 3 H), 3.34 (td, J = 11.9, 2.7 Hz, 1 H), 3.19 (dt, J = 12.3, 3.9 Hz, 1 H), 2.39-2.30 (m, 1 H), 2.18-2.05 (m, 3 H). ¹³C NMR (CDCl3, 75 MHz): δ = 155.9 (C), 151.3 (C), 146.8 (C), 144.9 (C), 128.5 (2 × CH), 125.0 (2 × CH), 123.7 (2 × CH), 114.2 (2 × CH), 58.8 (CH), 56.6 (CH), 55.4 (CH3), 51.2 (CH2), 43.5 (CH2), 34.2 (CH2). ESI-HRMS calculated for C18H20N2O3Cl [M+H]⁺ 347.1157, found 347.1160.

4-chloro-1,2-bis(4-methoxyphenyl)piperidine 5e (40%, 52 mg, dr: 20:80)

Trans 5e: Orange solid M.p. 98-100 °C. ¹H NMR (CDCl3, 300 MHz): δ = 7.16 (d, J = 8.8 Hz, 2 H), 6.92 (d, J = 8.8 Hz, 2 H), 6.72 (d, J = 8.8 Hz, 2 H), 6.68 (d, J = 8.8 Hz, 2 H), 4.53-4.46 (m, 2 H), 3.71 (s, 3 H), 3.68 (s, 3 H), 3.38 (td, J = 10.5, 2.7 Hz, 1 H), 3.17 (dt, J = 12.5, 4.4 Hz, 1 H), 2.29-2.17 (m, 3 H), 2.05-1.99 (m, 1 H). ¹³C NMR (CDCl3, 75 MHz): δ = 155.3 (C), 155.0 (C), 145.5 (C), 134.8 (C), 128.7 (2 × CH), 123.7 (2 × CH), 114.0 (2 × CH), 113.7 (2 × CH), 58.6 (CH), 57.1 (CH), 55.4 (CH3), 55.2 (CH3), 50.0 (CH2), 43.1 (CH2), 34.7 (CH2). ESI-HRMS calculated for C19H23NO2Cl [M+H]⁺ 332.1417, found 332.1417.

4-chloro-1-(4-methoxyphenyl)-2-p-tolylpiperidine 5f (90%, 113 mg, dr: 22:78)

Cis 5f: Orange oil ¹H NMR (CDCl3, 300 MHz): δ = 7.10 (d, J = 7.9 Hz, 2 H), 6.95 (d, J = 7.9 Hz, 2 H), 6.89 (d, J = 9.0 Hz, 2 H), 6.63 (d, J = 9.0 Hz, 2 H), 4.03 (tt, J = 11.4, 4.7 Hz, 1 H), 3.89 (dd, J = 11.1, 2.7 Hz, 1 H), 3.66 (s, 3 H), 3.38 (dt, J = 12.3, 3.5 Hz, 1 H), 2.79 (td, J = 12.0, 3.1 Hz, 1 H), 2.38- 2.32 (m, 1 H), 2.24-2.15 (m, 5 H), 2.01 (q, J = 12.0 Hz, 1 H). ¹³C NMR (CDCl3, 75 MHz): δ = 155.8 (C), 145.0 (C), 140.1 (C), 136.4 (C), 129.1 (2 × CH), 127.4 (2 × CH), 125.7 (2 × CH), 113.8 (2 × CH), 64.9 (CH), 57.6 (CH2), 57.2 (CH), 55.3 (CH3), 47.2 (CH2), 37.6 (CH2), 21.2(CH3). ESI-HRMS calculated for C19H23NOCl [M+H]⁺ 316.1468, found 316.1465. Trans 5f: Orange solid M.p. 102-104

°C. ¹H NMR (CDCl3, 300 MHz): δ = 7.14 (d, J = 7.9 Hz, 2 H), 6.98 (d, J = 7.9 Hz, 2 H), 6.92 (d, J = 9.0 Hz, 2 H), 6.68 (d, J = 9.0 Hz, 2 H), 4.55 (dd, J = 8.5, 3.7 Hz, 1 H), 4.44 (quint, J = 4.7 Hz, 1 H), 3.66 (s, 3 H), 3.38 (td, J = 10.0, 3.0 Hz, 1 H), 3.18 (dt, J = 12.6, 4.6 Hz, 1 H), 2.29-2.13 (m, 6 H), 2.04-2.00 (m, 1 H). ¹³C NMR (CDCl3, 75 MHz): δ = 155.8 (C), 145.5 (C), 139.7 (C), 136.2 (C), 129.1 (2 × CH), 127.5 (2 × CH), 123.4 (2 × CH), 114.1 (2 × CH), 58.9 (CH), 57.0 (CH), 55.4 (CH3), 49.9 (CH2), 43.1 (CH2), 34.7 (CH2), 21.1 (CH3). ESI-HRMS calculated for C19H23NOCl [M+H]⁺ 316.1468, found 316.1468.

4-chloro-2-isopropyl-1-(4-methoxyphenyl)piperidine 5g (98%, 105 mg, dr: 9:91)

Cis 5g: Orange oil ¹H NMR (CDCl3, 300 MHz): δ = 7.07 (d, J = 8.9 Hz, 2 H), 6.84 (d, J = 8.9 Hz, 2 H), 3.99 (tt, J = 11.5, 4.3 Hz, 1 H), 3.79 (s, 3 H), 3.07 (dt, J = 12.2, 3.6 Hz, 1 H), 2.75-2.67 (m, 2 H), 2.15-2.13 (m, 2 H), 1.99 (qd, J = 12.0, 4.3 Hz, 1 H), 1.71 (q, J = 11.5 Hz, 1 H), 1-70-1.65 (m, 1 H),